title: SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations.
abstract: Noonan syndrome (NS) is among the most common nonchromosomal disorders affecting development and growth. NS is caused by aberrant RAS-MAPK signaling and is genetically heterogeneous, which explains, in part, the marked clinical variability documented for this Mendelian trait. Recently, we and others identified SOS1 as a major gene underlying NS. Here, we explored further the spectrum of SOS1 mutations and their associated phenotypic features. Mutation scanning of the entire SOS1 coding sequence allowed the identification of 33 different variants deemed to be of pathological significance, including 16 novel missense changes and in-frame indels. Various mutation clusters destabilizing or altering orientation of regions of the protein predicted to contribute structurally to the maintenance of autoinhibition were identified. Two previously unappreciated clusters predicted to enhance SOS1's recruitment to the plasma membrane, thus promoting a spatial reorientation of domains contributing to inhibition, were also recognized. Genotype-phenotype analysis confirmed our previous observations, establishing a high frequency of ectodermal anomalies and a low prevalence of cognitive impairment and reduced growth. Finally, mutation analysis performed on cohorts of individuals with nonsyndromic pulmonic stenosis, atrial septal defects, and ventricular septal defects excluded a major contribution of germline SOS1 lesions to the isolated occurrence of these cardiac anomalies.
authors.affiliation: IRCCS Casa Sollievo della Sofferenza, Laboratorio Mendel, San Giovanni Rotondo, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lepri
authors.forename: Alessandro
authors.initials: A
authors.lastname: De Luca
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Stella
authors.forename: Cesare
authors.initials: C
authors.lastname: Rossi
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Baldassarre
authors.forename: Francesca
authors.initials: F
authors.lastname: Pantaleoni
authors.forename: Viviana
authors.initials: V
authors.lastname: Cordeddu
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Williams
authors.forename: Maria L
authors.initials: ML
authors.lastname: Dentici
authors.forename: Viviana
authors.initials: V
authors.lastname: Caputo
authors.forename: Serenella
authors.initials: S
authors.lastname: Venanzi
authors.forename: Michela
authors.initials: M
authors.lastname: Bonaguro
authors.forename: Ines
authors.initials: I
authors.lastname: Kavamura
authors.forename: Maria F
authors.initials: MF
authors.lastname: Faienza
authors.forename: Alba
authors.initials: A
authors.lastname: Pilotta
authors.forename: Franco
authors.initials: F
authors.lastname: Stanzial
authors.forename: Francesca
authors.initials: F
authors.lastname: Faravelli
authors.forename: Orazio
authors.initials: O
authors.lastname: Gabrielli
authors.forename: Bruno
authors.initials: B
authors.lastname: Marino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Neri
authors.forename: Margherita Cirillo
authors.initials: MC
authors.lastname: Silengo
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Ferrero
authors.forename: Isabella
authors.initials: I
authors.lastname: Torrrente
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.forename: Laura
authors.initials: L
authors.lastname: Mazzanti
authors.forename: Maria C
authors.initials: MC
authors.lastname: Digilio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D006344:Heart Septal Defects, Atrial / Q000235:genetics; D006345:Heart Septal Defects, Ventricular / Q000235:genetics; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D007438:Introns; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D009154:Mutation; D020125:Mutation, Missense / Q000235:genetics; D009634:Noonan Syndrome / Q000175:diagnosis* / Q000235:genetics*; D011487:Protein Conformation; D011666:Pulmonary Valve Stenosis / Q000235:genetics; D020837:SOS1 Protein / Q000737:chemistry / Q000235:genetics*
chemical_list: D020837:SOS1 Protein; D020929:Mitogen-Activated Protein Kinase Kinases